Shippenberg T S, LeFevour A, Heidbreder C
Behavioral Pharmacology and Genetics Section, NIDA Intramural Research Program, Baltimore, Maryland, USA.
J Pharmacol Exp Ther. 1996 Feb;276(2):545-54.
A place preference conditioning procedure was used to examine the influence of kappa-opioid receptor ligands upon the development of sensitization to the conditioned rewarding effects of cocaine. Previous exposure to cocaine (10-20 mg/kg; i.p.; days 1-5) resulted in an enhancement of the conditioned rewarding effects of this agent, e.g., sensitization. Thus, doses of cocaine (5.0-10.0 mg/kg; i.p.) that failed to produce place preferences in control rats produced significant place preferences in cocaine-experienced animals. In animals that had received the kappa-agonist U50,488H (5.0 mg/kg; s.c.) in combination with the repeated cocaine treatment regimen, no enhancement of cocaine-induced place conditioning was seen. Similarly, the kappa-agonist U69593 administered on days 1 to 5 or only on days 3 to 5 of the cocaine treatment regimen prevented the enhanced response to cocaine. This effect occurred after either systemic (0.04-0.16 mg/kg; s.c.) or intracerebroventricular (1.0 mg) treatment and was abolished by the kappa-opioid receptor antagonist, nor-binaltorphimine. In contrast to its effects when administered in combination with cocaine, prior administration of U69593, alone, failed to modify the conditioned response to cocaine. Microdialysis studies revealed a marked elevation of extracellular dopamine levels within the ventral striatum after repeated cocaine administration. In animals that had received U69593 in combination with cocaine, no elevation of dopamine was seen. These data demonstrate that sensitization develops to the conditioned rewarding effects of cocaine and that the activation of central nervous system kappa-opioid receptors prevents the development of this phenomenon. An involvement of the mesolimbic dopamine system in mediating the interaction of kappa-agonists with cocaine is suggested.
采用位置偏爱条件化程序来研究κ-阿片受体配体对可卡因条件性奖赏效应敏化发展的影响。先前给予可卡因（10 - 20mg/kg；腹腔注射；第1 - 5天）导致该药物条件性奖赏效应增强，即敏化。因此，在对照大鼠中未能产生位置偏爱的可卡因剂量（5.0 - 10.0mg/kg；腹腔注射）在有可卡因经历的动物中产生了显著的位置偏爱。在接受κ-激动剂U50,488H（5.0mg/kg；皮下注射）并结合重复可卡因治疗方案的动物中，未观察到可卡因诱导的位置条件化增强。同样，在可卡因治疗方案的第1至5天或仅第3至5天给予κ-激动剂U69593可防止对可卡因的反应增强。这种效应在全身（0.04 - 0.16mg/kg；皮下注射）或脑室内（1.0mg）给药后出现，并被κ-阿片受体拮抗剂去甲二氢吗啡酮消除。与与可卡因联合给药时的效应相反，单独预先给予U69593未能改变对可卡因的条件反应。微透析研究显示，重复给予可卡因后腹侧纹状体内细胞外多巴胺水平显著升高。在接受U69593与可卡因联合给药的动物中，未观察到多巴胺升高现象。这些数据表明对可卡因的条件性奖赏效应会产生敏化，并且中枢神经系统κ-阿片受体的激活可防止这种现象的发展。提示中脑边缘多巴胺系统参与介导κ-激动剂与可卡因的相互作用。
